The pathogenesis of Parkinson's Disease (PD) involves death of dopaminergic neurons in the substantia nigra and Lewy bodies in the substantia nigra and other brain regions, including brainstem monominergic neurons, and neurons in the cerebral cortex. Alpha-Synuclein mutations cause autosomal dominant forms of PD clinically indistinguishable from sporadic PD. In addition, alpha-synuclein is a component of the Lewy bodies in both PD and in Diffuse Lewy Body disease. In Specific Aim #1 we will identify protein interactors for alpha-synuclein using the yeast two- hybrid system and confirm the interactions using biochemical techniques. In Specific Aim #2 we will characterize the cellular pattern of expression of these interactors in comparison with alpha-synuclein. In Specific Aim #3 we will make a cell model which reproduces some of the features of PD using transient and stable expression of alpha-synuclein and interacting proteins in cell culture. We will study the pathways of cell death which are activated in this model. Taken together these studies will shed light on the molecular and cellular pathogenesis of PD and provide models for testing of experimental therapeutics.